Pd-catalyzed conversion of aryl chlorides, triflates, and nonaflates to nitroaromatics

Article abstract of DOI:10.1021/ja905768k

(Chemical Equation Presented) An efficient Pd catalyst for the transformation of aryl chlorides, triflates, and nonaflates to nitroaromatics has been developed. This reaction proceeds under weakly basic conditions and displays a broad scope and excellent

Full text of DOI:10.1021/ja905768k

Published on Web 08/19/2009
Pd-Catalyzed Conversion of Aryl Chlorides, Triflates, and Nonaflates to
Nitroaromatics
Brett P. Fors and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received July 12, 2009; E-mail: sbuchwal@mit.edu
Table 1. Pd-Catalyzed Formation of 4-Nitro-n-butylbenzene
Aromatic nitro compounds are of great importance to a variety
of disciplines. They can be found in an array of pharmaceuticals,1
dyes,2 and materials.3 Moreover, they are important entities in
synthesis and can participate in a range of useful transformations.4
Most commonly, nitrobenzenes are synthesized via electrophilic
aromatic substitution using HNO3 and a strong acid or with
dinitrogen pentoxide.4 However, these methods suffer from issues
of poor regioselectivity and imperfect functional group tolerance.
Further, the application of these reactions is particularly problematic
for the nitration of heteroaromatics. More recently, Prakash and
Olah disclosed a method for the conversion of aryl boronic acids
to aryl nitro compounds.5 This was followed by a report from Saito
disclosing a copper catalyst for the transformation of aryl iodides
to nitrobenzenes.6 These processes were important advances in this
field and provided nitration protocols complementary to known
chemistry; however, the substrate scope of these reactions is limited
and does not include heterocycles.
entry
L
5% PTC
yielda
entry
L
5% PTC
yielda
1
2
3
4
5
1
1
1
1
2
-
26%
52%
3%
33%
0%
6
7
8
9
10
3
4
5
1
1
TDA
TDA
TDA
-
10%
0%
TDA
TBACl
15-C-5
TDA
0%
2%b
99%c
TDA
a 4-Chloro-n-butylbenzene (1 mmol), NaNO2 (2.0 mmol), Pd2(dba)3
(0.5 mol %), ligand (1.2 mol %), t-BuOH (2 mL), 110 °C, 24 h; GC
yields. b (TBA)NO2 was used. c Reaction temperature was 130 °C.
and the methoxy substituent ortho to the phosphine are critical to
the reactivity of this catalyst system.
We observed that the yield of the reaction increased as the
amount of TDA was increased from 0 to 5 mol %. However, the
amount of product generated in these reactions dropped quickly
when more than 5% TDA was used (Figure 2).11 We reasoned that
higher concentrations of nitrite in solution could oxidize Pd(0) or
the ligand, which would explain the lower yields at higher loadings
of TDA. To test this postulate, we ran the reaction with a soluble
source of nitrite (tetrabutylammonium nitrite) and obtained only
2% 4-nitro-n-butylbenzene (Table 1, entry 9). These studies show
that having the optimal amount of nitrite in solution is essential to
the outcome of the reaction.
Herein, we report a general Pd catalyst for the conversion of
aryl chlorides, triflates, and nonaflates to nitroaromatics.7 This
protocol circumvents issues of regioselectivity and proceeds ef-
ficiently under weakly basic conditions, allowing for excellent
functional group compatibility. Moreover, it enables the formation
of nitroarenes that cannot be accessed effectively by other means,
most notably nitro-substituted heteroaryl compounds. Mechanistic
insight into the “transmetalation” step of this catalytic process is
also provided.
We began our studies by examining the reaction of 4-chloro-n-
butylbenzene with commercially available nitrite sources. We
hypothesized that a catalyst based on ligand 1 (Figure 1), which
we have shown to be effective in amidation reactions of aryl
chlorides,8 would be useful for this transformation, since we
expected that N-Pd bond formation would be difficult, as in the
latter transformation. Use of 0.5 mol % Pd2(dba)3, 1.2 mol % 1,
and sodium nitrite in t-BuOH afforded the desired 4-nitro-n-
butylbenzene in 26% yield (Table 1). Since sodium nitrite is
sparingly soluble in t-BuOH, we reasoned that use of a phase-
transfer catalyst (PTC) might be beneficial. Adding 5 mol % tris(3,6-
dioxaheptyl)amine (TDA) improved the yield to 52%, whereas the
use of other PTCs did not have a positive influence on the outcome
of the reaction.
By increasing the reaction temperature, we were able to convert
4-chloro-n-butylbenzene to the desired nitro product in virtually
quantitative yield (Table 1, entry 11). Using these conditions, we
set out to explore the scope of the Pd-catalyzed transformation of
aryl chlorides to nitroaromatics using a catalyst based on ligand 1
(Table 2). Ortho substituents as well as acid-sensitive functional
groups such as an acetal, a pyrrole, and a free alcohol were all
well-tolerated. Nitroarenes containing electron-withdrawing groups
or amines in the para position and electron-donating substituents
in the meta position were synthesized in high yields with this
method; these compounds cannot be efficiently formed through
traditional nitration protocols. Nitro heteroaromatics could also be
Catalysts based on other biarylphosphine ligands (2,8 3,9 4, and
5)10 gave little to no desired product in these reactions. This
demonstrates that in ligand 1, both the di-tert-butylphosphino group
Figure 2. Effect of TDA on the yield of the Pd-catalyzed formation of
4-nitro-n-butylbenzene.
Figure 1. Biarylphosphine ligands.
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12898 J. AM. CHEM. SOC. 2009, 131, 12898–12899
10.1021/ja905768k CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Conversion of Aryl Chlorides to Nitroaromaticsa
Table 3. Conversion of Aryl Triflates and Nonaflates to
Nitroaromaticsa
a ArX (1 mmol), NaNO2 (2.0 mmol), Pd2(dba)3 (0.5 mol %), 1 (1.2
mol %), t-BuOH (2 mL), 130 °C, 24 h; isolated yields, average of two
runs. b Pd2(dba)3 (2.5 mol %), 1 (6 mol %).
a ArCl (1 mmol), NaNO2 (2.0 mmol), Pd2(dba)3 (0.5 mol %), 1 (1.2
mol %), t-BuOH (2 mL), 130 °C, 24 h; isolated yields, average of two
runs. b Pd2(dba)3 (2.5 mol %), 1 (6 mol %).
corresponding products in good to excellent yields (Table 3),
including those containing esters and nitriles; heteroaryl triflates
were also transformed with high efficiencies.
prepared in good to excellent yields. For example, 5- and 7-chlor-
oindole were transformed to the corresponding nitroindoles in good
yields without the need of a protecting group. This catalyst system
is complementary to current nitration protocols and allows for the
synthesis of nitroaromatic compounds that are not readily accessible
via other means.
In summary, an effective catalyst for the conversion of aryl
chlorides, triflates, and nonaflates to nitroaromatics has been
developed. This method is complementary to previous nitration
protocols and evades issues of regioselectivity and functional group
compatibility. It has also been shown that the rate of transmetalation
follows the order Cl > Br > I in these reactions. Further studies to
better understand the mechanism of the reaction and extend its scope
to aryl iodides, bromides, and tosylates are currently underway in
our laboratory.
On the basis of the broad scope this catalyst displayed for the
nitration of aryl chlorides, we decided to explore nitrations of aryl
bromides and iodides. Under the optimized reaction conditions, 3,5-
dimethylbromobenzene (6) and 3,5-dimethyliodobenzene (7) gave
the desired products in 44 and 0% yield, respectively (Figure 3).
In order to aid our interpretation of this result, competition
experiments involving the aryl bromide or iodide versus the aryl
chloride were performed. In experiment A, where a 1:1 mixture of
6 and 8 was subjected to the reaction conditions, yields of 44 and
0% for the aryl bromide-derived and aryl chloride-derived coupling
products, respectively, were observed. In experiment B, where a
1:1 mixture of 7 and 8 was used, no nitroaromatic products were
formed. These results demonstrate that the catalyst undergoes
oxidative addition with the aryl iodide or bromide faster than with
the aryl chloride and that transmetalation is the slow (problematic)
step for these processes.12 Moreover, they establish that the rate of
transmetalation follows the order Cl > Br > I in these reactions.
On the basis of these results and previous findings in our group,10
we postulated that aryl triflates and nonaflates would react with an
accelerated rate of transmetalation and be suitable substrates for
these reactions. With a catalyst consisting of 1 and Pd2(dba)3, an
array of aryl nonaflates and triflates were converted to the
Acknowledgment. We thank the National Institutes of Health
(NIH) for financial support of this project (GM-58160). We thank
Merck, BASF, and Nippon Chemical for additional support. B.P.F.
thanks Merck and the William Asbornsen Albert Memorial Fund
for fellowships.
Supporting Information Available: Procedural and spectral data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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Figure 3. Reactions of aryl bromides and iodides.
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